Phenylalkyloxy-phenyl derivatives

ABSTRACT

The present invention relates to certain phenalkyloxy-phenyl derivatives of formula (I) and analogs, to a process for preparing such compounds, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.

FIELD OF INVENTION

[0001] The present invention relates to certain phenalkyloxyphenylderivatives of formula I and analogs, to a process for preparing suchcompounds, having the utility in clinical conditions associated withinsulin resistance, to methods for their therapeutic use and topharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

[0002] Insulin resistance, defined as reduced sensitivity to the actionsof insulin in the whole body or individual tissues such as skeletalmuscle, myocardium, fat and liver prevail in many individuals with orwithout diabetes mellitus. The insulin resistance syndrome, IRS, refersto a cluster of manifestations including insulin resistance withaccompanying hyperinsulinemia, possibly type 2 diabetes mellitus,arterial hypertension, central (visceral) obesity, dyslipidemia observedas deranged lipoprotein levels typically characterised by elevated VLDL(very low density lipoproteins) and reduced HDL (high densitylipoproteins) concentrations, the presence of small, dense LDL (LowDensity Lipoprotein) particles and reduced fibrinolysis.

[0003] Recent epidemiological research has documented that individualswith insulin resistance run a greatly increased risk of cardiovascularmorbidity and mortality, notably suffering from myocardial infarctionand stroke. In non-insulin dependent diabetes mellitus theseatherosclerosis related conditions cause up to 80% of all deaths.

[0004] In clinical medicine there is at present only limited awarenessof the need to increase the insulin sensitivity in IRS and thus tocorrect the dyslipidemia which is considered to cause the acceleratedprogress of atherosclerosis.

[0005] Furthermore there is at present no pharmacotherapy available toadequately correct the metabolic disorders associated with IRS. To date,the treatment of type 2 diabetes mellitus has been focused on correctionof the deranged control of carbohydrate metabolism associated with thedisease. Stimulation of endogenous insulin secretion by means ofsecretagogues, like sulphonylureas, and if necessary administration ofexogenous insulin are methods frequently used to normalise blood sugarbut that will, if anything, further enhance insulin resistance and willnot correct the other manifestations of IRS nor reduce cardiovascularmorbidity and mortality. In addition such treatment involves asignificant risk of hypoglycemia with associated complications.

[0006] Other therapeutic strategies have focused on aberrations inglucose metabolism or absorption, including biguanides, such asmethformin, or glucosidase inhibitors, such as acarbose. Although theseagents have been efficacious to a degree, their limited clinical effectis associated with side effects.

[0007] A novel therapeutic strategy involves the use of insulinsensitising agents, such as the thiazolidinediones which at least inpart mediate their effects via an agonistic action on nuclear receptors.Ciglitazone is the prototype in this class. In animal models of IRSthese compounds seem to correct insulin resistance and the associatedhypertriglyceridemia and hyperinsulinemia, as well as hyperglycemia indiabetes, by improving insulin sensitivity via an effect on lipidtransport and handling, leading to enhanced insulin action in skeletalmuscle, liver and adipose tissue.

[0008] Ciglitazone as well as later described thiazolidinediones inclinical development either have been discontinued reportedly due tounacceptable toxicity or show inadequate potency.

[0009] Therefore there is a need for new and better compounds withinsulin sensitising properties.

[0010] Co-pending PCT application SE00/02383 discloses the use ofcompounds of the general formula (I) for the treatment of conditionsrelated to insulin resistance

[0011] and stereo and optical isomers and racemates thereof as well aspharmaceutically acceptable salts, prodrugs, solvates and crystallineforms thereof, in which formula A is situated in the ortho, meta or paraposition and represents

[0012] wherein

[0013] R is cyano, when X is 0, and when X is 1 then R is;

[0014] —BR^(a) or SCOR^(a), wherein B is O, S, SO or SO₂, wherein R^(a)represents hydrogen, alkyl, aryl or alkylaryl and wherein the alkyl,aryl or alkylaryl group is optionally substituted one or more times byR^(b), wherein R^(b) represents alkyl, aryl, alkylaryl, cyano,—NR^(c)R^(c), ═O, halogen, —OH, —SH, -Oalkyl, -Oaryl, -Oalkylaryl,—COR^(c), —SR^(d), —SOR^(d), or —SO₂R^(d), wherein R^(c) representshydrogen, alkyl, aryl or alkylaryl and R^(d) represents alkyl, aryl oralkylaryl;

[0015] —BB¹R^(a), wherein B¹ is O when B is S, SO or SO₂ or B¹ is S, SOor SO₂ when B is O, and wherein B and R^(a) are as defined above, oralternatively R is NR^(a)R^(a), wherein each R^(a) is the same ordifferent and wherein R^(a) is defined above;

[0016] R² represents alkyl, halogen, aryl, alkylaryl, alkenyl, alkynyl,nitro or cyano and wherein the alkyl, aryl, alkenyl, alkylaryl andalkynyl group is optionally substituted by R^(b), wherein R^(b) is asdefined above;

[0017] —BR^(a) wherein B and R^(a) are as defined above;

[0018] —SO₂NR^(a)R^(f) wherein R^(f) represents hydrogen, alkyl, acyl,aryl or alkylaryl and R^(a) is as defined above;

[0019] —SO₂OR^(a), wherein R^(a) is as defined above;

[0020] —OCONR^(f)R^(a), wherein R^(f) and R^(a) are as defined above;

[0021] —NR^(c)COOR^(d), wherein R^(c) and R^(d) are as defined above;

[0022] —NR^(c)COR^(a), wherein R^(c) and R^(a) are as defined above;

[0023] —CONR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;

[0024] —NR^(c)SO₂R^(d), wherein R^(c) and R^(d) are as defined above;

[0025] —NR^(c)CONR^(a)R^(k), wherein R^(a) and R^(c) are as definedabove and R^(k) represents hydrogen, alkyl, aryl, or alkylaryl;

[0026] alternatively R² is —NR^(c)R^(a), wherein R^(c) and R^(a) are asdefined above;

[0027] R¹, R³ and R⁴ are the same or different and each representshydrogen, alkyl, aryl, alkenyl, alkynyl, cyano, halogen or alkylarylwherein the alkyl, aryl, alkenyl or alkynyl group is optionallysubstituted by R^(b);

[0028] n is an integer from 1 to 6;

[0029] X is an integer 0 or 1;

[0030] m is an integer 0 or 1;

[0031] D is situated in the ortho, meta or para position and representsalkyl, acyl, aryl, alkylaryl, halogen, —CN and NO₂, wherein the alkyl,aryl, or alkylaryl group is optionally substituted by R^(b);

[0032] —NR^(c)COOR^(a), wherein R_(c) and R^(a) are as defined above;

[0033] —NR^(c)COR^(a), wherein R^(c) and R^(a) are as defined above;

[0034] —NR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;

[0035] —NR^(c)SO₂R^(d), wherein R^(c) and R^(d) are as defined above;

[0036] —NR^(c)CONR^(k)R^(c), wherein R^(a), R^(c) and R^(k) are asdefined above;

[0037] —NR^(c)CSNR^(a)R^(k), wherein R^(a), R^(c) and R^(k) as definedabove;

[0038] —OR^(a), wherein R^(a) is as defined above;

[0039] —OSO₂R^(d), wherein R^(d) is as defined above;

[0040] —SO₂R^(d), wherein R^(d) is as defined above;

[0041] —SOR^(d), wherein R^(d) is as defined above;

[0042] —SR^(c), wherein R^(c) is as defined above;

[0043] —SO₂NR^(a)R^(f), wherein R^(f) and R^(a) are as defined above;

[0044] —SO₂OR^(a), wherein R^(a) is as defined above;

[0045] —CONR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;

[0046] —OCONR^(f)R^(a), wherein R^(f) and R^(a) are as defined above;

[0047] D′ is situated in the ortho, meta or para position and representshydrogen, alkyl, acyl, aryl, alkylaryl, halogen, —CN, —NO₂,

[0048] —NR^(f)R^(b), wherein R^(f) and R^(b) are as defined above;

[0049] —OR^(f), wherein R^(f) is as defined above;

[0050] —OSO₂R^(d), wherein R^(d) is as defined above;

[0051] D″ is situated in the ortho, meta or para position and representshydrogen, alkyl, acyl, aryl, alkylaryl, halogen, —CN, —NO₂,

[0052] —NR^(f)R^(b) wherein R^(f) and R^(b) are as defined above;

[0053] —OR^(f), wherein R^(f) is as defined above;

[0054] —OSO₂R^(d), wherein R^(d) is as defined above.

[0055] Compounds disclosed in this application are disclaimed from thepresent application.

DESCRIPTION OF THE INVENTION

[0056] The invention relates to compounds of the general formula (I)

[0057] and stereo and optical isomers and racemates thereof as well aspharmaceutically acceptable salts, prodrugs, solvates and crystallineforms thereof, in which formula A is situated in the ortho, meta or paraposition and represents

[0058] wherein R is cyano, when x is 0, and when x is 1 then R is:

[0059] —BR^(a), OCOR^(a) or SCOR^(a), wherein B is O, S, SO or SO₂wherein R^(a) represents hydrogen, alkyl, aryl, alkylaryloxy oralkylaryl and wherein the alkyl, aryl or alkylaryl group is optionallysubstituted one or more times by R^(b), wherein R^(b) represents alkyl,aryl, alkylaryl, cyano, —NR^(c)R^(c), ═O, halogen, —OH, —SH, -Oalkyl,-Oaryl, -Oalkylaryl, —COR^(c), —SR^(d), —SOR^(d), or —SO₂R^(d)(preferably R^(b) is selected from alkyl, aryl, alkylaryl, cyano, —NH₂,═O, halogen and —OH), wherein R^(c) represents hydrogen, alkyl, aryl oralkylaryl and R^(d) represents alkyl, aryl or alkylaryl;

[0060] —BB¹R^(a), wherein B¹ is O when B is S, SO or SO₂ or B¹ is S, SOor SO₂ when B is O, and wherein B and R^(a) are as defined above;

[0061] or alternatively R is —NR^(a)R^(a), wherein each R^(a) is thesame or different and wherein R^(a) is defined above;

[0062] R² represents alkyl, halogen, aryl, alkylaryl, alkenyl, alkynyl,nitro or cyano and wherein the alkyl, aryl, alkenyl, alkylaryl andalkynyl group is optionally substituted by R^(b), wherein R^(b) is asdefined above;

[0063] —BR^(a) wherein B and R^(a) are as defined above;

[0064] —SO₂NR^(a)R^(f), wherein R^(f) represents hydrogen, alkyl, acyl,aryl or alkylaryl and R^(a) is as defined above;

[0065] —SO₂OR^(a), wherein R^(a) is as defined above;

[0066] —OCONR^(f)R^(a), wherein R^(f) and R^(a) are as defined above;

[0067] —NRC^(c)COOR^(d), wherein R^(c) and R^(d) are as defined above;

[0068] —NR^(c)COR^(a), wherein R^(c) and R^(a) are as defined above;

[0069] —CONR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;

[0070] —NR^(c)SO₂R^(d), wherein R^(c) and R^(d) are as defined above;

[0071] —NR^(c)CONR^(a)R^(k), wherein R^(a) and R^(c) are as definedabove and R^(k) represents hydrogen, alkyl, aryl, or alkylaryl;

[0072] alternatively R² is —NR^(c)R^(a), wherein R^(c) and R^(a) are asdefined above;

[0073] R¹, R³ and R⁴ are the same or different and each representshydrogen, alkyl, aryl, alkenyl, alkynyl, cyano, halogen or alkylarylwherein the alkyl, aryl, alkenyl or alkynyl group is optionallysubstituted by R^(b);

[0074] x is an integer 0 or 1 (preferably x is 1);

[0075] E represents a group of formula i

[0076] or a group of formula ii

[0077] wherein X is S, O, NR^(Z) wherein R^(Z) is as defined below, CH═Nor N═CH and Y represents CH or N; or X represents —CH═CH— and Yrepresents N;

[0078] or E represents a group of formula iii

[0079] wherein X is S, O, NR^(z), —CH═N or —N═CH and Y represents CH orN; or X represents —CH═CH— and Y represents N wherein R^(Z) representshydrogen, alkyl, aryl, alkyloxyaryl, alkylbiphenylyl, alkoxyalklylaryl,acylbiphenylyl, alkylphthalimido, SO₂R^(Z), COR^(d) or alkylaryl(preferably R^(Z) is selected from hydrogen, alkyl and alkyaryl) andwherein the alkyl, aryl, alkyloxyaryl or alkylaryl group is optionallysubstituted one or more times by R^(b), wherein R^(b) represents alkyl,aryl, alkylaryl, cyano, —NR^(c)R^(c), ═O, halogen, —OH, —SH, -Oalkyl,-Oaryl, -Oalkylaryl, —COR^(c), —SR^(d), SOR^(d), or SO₂R^(d) (preferablyR^(b) is selected from alkyl, aryl, alkylaryl, cyano, —NH₂, ═O, halogenand —OH), wherein R^(c) represents hydrogen, alkyl, aryl or alkylaryland R^(d) represents alkyl, aryl or alkylaryl;

[0080] or E represents a group of formula iv

[0081] C3-C8cycloalkyl iv

[0082] or E represents a group of formula v

[0083] which is linked to L through the nitrogen atom;

[0084] or E represents a group of formula vi

[0085] or E represents a group of formula vii

[0086] wherein D represents H, alkyl, acyl, aryl, alkylaryl, halogen,—CN and NO₂, wherein the alkyl, aryl, or alkylaryl group is optionallysubstituted by R^(b);

[0087] —NR^(c)COOR^(a), wherein R^(c) and R^(a) are as defined above;

[0088] —NR^(c)COR^(a), wherein R^(c) and R^(a) are as defined above;

[0089] —NR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;

[0090] —NR^(c)SO₂R^(d), wherein R^(c) and R^(d) are as defined above;

[0091] —NR^(c)CONR^(k)R^(c), wherein R^(a), R^(c) and R^(k) are asdefined above;

[0092] —NR^(c)CSNR^(a)R^(k), wherein R^(a), R^(c) and R^(k) are asdefined above;

[0093] —OR^(a), wherein R^(a) is as defined above;

[0094] —OSO₂R^(d), wherein R^(d) is as defined above;

[0095] —SO₂R^(d), wherein R^(d) is as defined above;

[0096] —SOR^(d), wherein R^(d) is as defined above;

[0097] —SR^(c), wherein R^(c) is as defined above;

[0098] —SO₂NR^(a)R^(f), wherein R^(f) and R^(a) are as defined above;

[0099] SO₂OR^(a), wherein R^(a) is as defined above;

[0100] —CONR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;

[0101] —OCONR^(f)R^(a), wherein R^(f) and R^(a) are as defined above;

[0102] m is an integer 0 or 1 (preferably m is 1);

[0103] D′ represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen,—CN, —NO₂, —NR^(f)R^(b), wherein R^(f) and R^(b) are as defined above;

[0104] —OR^(f), wherein R^(f) is as defined above;

[0105] —OSO₂R^(d), wherein R^(d) is as defined above;

[0106] CH═CH—COOR^(c) wherein R^(c) is as defined above;

[0107] D″ is represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen,—CN, —NO₂, —NR^(f)R^(b) wherein R^(f) and R^(b) are as defined above;

[0108] —OR^(f), wherein R^(f) is as defined above;

[0109] —OSO₂R^(d), wherein R^(d) is as defined above;

[0110] L represents O or an alkylene chain having from 1 to 6 carbonatoms optionally interrupted or terminated by one or more of thefollowing O, S, SO, SO₂, CO, NR^(t), CONR^(t), NR^(t)CO, OC(O)NR^(t),NR^(t)C(O)O, SO₂NR^(t), R^(t)NSO₂ or R^(t)N—CO—NR^(t) provided that theyare not attached to each other and wherein the alkylene chain carbonsmay be substituted by one or more alkyl, hydroxy, aryl, aryloxy,arylthio, alkylaryl, cyano, NR^(c)R^(c), halo, SH, Oalkylaryl, COR^(c),—COR^(c), —SR^(d), —SOR^(d), or —SO₂R^(d), or alkoxy and with theproviso that when E is a group of formula i then L does not represent[CH₂]_(n)—CH₂—O in which n is an integer from 1 to 6; and R^(t)represents H, alkyl, aryl, alkylaryl, alkylcycloalkyl, oralkylbiphenylyl wherein each alkyl chain may be substituted by one ormore hydroxy or alkoxy and is optionally interrupted by one or more Oprovided that two hetero atoms are not attached to the same carbon atom.

[0111] Preferably L represents O, a C1, C2, C3, C4 or C5 alkylene chainor a group of formula (CH₂)_(a)Z¹(CH₂)_(b)Z² wherein a is 0,1, 2 or 3;Z¹ is absent or represents O, S, SO, SO₂, CO, NR^(t), CONR^(t),NR^(t)CO, OC(O)NR^(t), NR^(t)C(O)O, SO₂NR^(t), R^(t)NSO₂ orR^(t)N—CO—NR^(t), b is 1, 2 or 3 and Z² is absent or represents O, S,SO, SO₂, CO, NR^(t), CONR^(t), NR^(t)CO, OC(O)NR^(t), NR^(t)C(O)O,R^(t)N—CO—NR^(t) wherein R^(t) is as defined above and all of thealkylene chains are optionally substituted by one or more of thefollowing alkyl, hydroxy, aryl, aryloxy, arylthio, alkylaryl, cyano,NR^(c)R^(c), halo, SH, Oalkylaryl, COR^(c), —COR^(c), —SR^(d), —SOR^(d),or —SO₂R^(d), or alkoxy wherein R^(d) is as defined above, provided thatZ¹ and Z² are not absent simultaneously.

[0112] “Pharmaceutically acceptable salt”, where such salts arepossible, includes both pharmaceutically acceptable acid and baseaddition salts. A suitable pharmaceutically-acceptable salt of acompound of Formula I is, for example, an acid-addition salt of acompound of Formula I which is sufficiently basic, for example anacid-addition salt with an inorganic or organic acid such ashydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleicacid; or, for example a salt of a compound of Formula I which issufficiently acidic, for example an alkali or alkaline earth metal saltsuch as a sodium, calcium or magnesium salt, or an ammonium salt, or asalt with an organic base such as methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0113] In vivo hydrolysable esters of the compounds of Formula I arejust one type of prodrug of the parent molecule. Other prodrugs of theparent molecule are envisaged such as amide prodrugs, and can beprepared by routine methodology well within the capabilities of someoneskilled in the art. Prodrugs of the compound of Formula I are within thescope of the invention. Various prodrugs are known in the art. Forexamples of such prodrug derivatives, see:

[0114] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)and Methods in Enzymology. 42: 309-396, edited by K. Widder, et al.(Academic Press, 1985);

[0115] b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p.113-191 (1991);

[0116] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992);

[0117] d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences,77:285 (1988); and

[0118] e) N. Kakeya, et al., Chem Pharm Bull, 32:692 (1984).

[0119] The preferred examples of prodrugs include in vivo hydrolysableesters of a compound of the Formula 1. Suitablepharmaceutically-acceptable esters for carboxy include C₁₋₈alkyl esters,C₅₋₈cycloalkyl esters, cyclic amine esters, C₁₋₆alkoxymethyl esters forexample methoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethylwherein alkyl, cycloalkyl and cyclicamino groups are optionallysubstituted by, for example, phenyl, heterocyclcyl, alkyl, amino,alkylamino, dialkylamino, hydroxy, alkoxy, aryloxy or benzyloxy, and maybe formed at any carboxy group in the compounds of this invention.Particularly preferred compounds of the present invention are where Rrepresents prodrugs for a hydroxy group.

[0120] It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It is to be understood that the present inventionencompasses all such solvated forms.

[0121] When the substituent OR^(a) represents an alkylaryl group, thepreferred alkylaryl is benzyl.

[0122] Throughout the specification and the appended claims, a givenchemical formula or name shall encompass all stereo and optical isomersand racemates thereof as well as mixtures in different proportions ofthe separate enantiomers, where such isomers and enantiomers exist, aswell as pharmaceutically acceptable salts thereof and solvates thereofsuch as for instance hydrates. Isomers may be separated usingconventional techniques, e.g. chromatography or fractionalcrystallisation. The enantiomers may be isolated by separation ofracemate for example by fractional crystallisation, resolution or HPLC.The diastereomers may be isolated by separation of isomer mixtures forinstance by fractional crystallisation, HPLC or flash chromatography.Alternatively the stereoisomers may be made by chiral synthesis fromchiral starting materials under conditions which will not causeracemisation or epimerisation, or by derivatisation, with a chiralreagent. All stereoisomers are included within the scope of theinvention.

[0123] The following definitions shall apply throughout thespecification and the appended claims.

[0124] Unless otherwise stated or indicated, the term “alkyl” denoteseither a straight or branched alkyl group having from 1 to 12 carbonatoms or a cyclic alkyl atom having from 3 to 6 carbon atoms, the alkylbeing substituted or unsubstituted. The term “lower alkyl” denoteseither a straight or branched alkyl group having from 1 to 3 carbonatoms or a cyclic alkyl having 3 carbon atoms, the alkyl beingsubstituted or unsubstituted. Examples of said alkyl and lower alkylinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl aswell as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferredalkyl groups methyl, ethyl, propyl, isopropyl and tertiary butyl.

[0125] Unless otherwise stated or indicated, the term “alkoxy” denotes agroup O-alkyl, wherein alkyl is as defined above.

[0126] Unless otherwise stated or indicated, the term “halogen” shallmean fluorine, chlorine, bromine or iodine, preferably fluorine.

[0127] Unless otherwise stated or indicated, the term “aryl” denotes asubstituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, ora fused ring system of any of these groups, such as naphthyl.

[0128] Unless otherwise stated or indicated, the term “substituted”denotes an alkyl or an aryl group as defined above which is substitutedby one or more alkyl, alkoxy, alkylthio, halogen, amino, thiol, nitro,hydroxy, acyl, aryl or cyano groups.

[0129] Unless otherwise stated or indicated, the term “alkylaryl”denotes a

[0130] wherein n is an integer 1 to 6 and R^(r) and R^(i) are the sameor different and each represents hydrogen or an alkyl or aryl group asdefined above.

[0131] Unless otherwise stated or indicated, the term “acyl” denotes agroup

[0132] wherein R^(j) is hydrogen, alkyl, alkoxy, aryl and alkylaryl asdefined above.

[0133] Unless otherwise stated or indicated, the terms “alkenyl” and“alkynyl” denote a straight or branched, substituted or unsubstitutedunsaturated hydrocarbon group having one or more double or triple bondsand having a maximum of 6 carbon atoms, preferably 3 carbon atoms.

[0134] Unless otherwise stated or indicated the term “protective group”denotes a protecting group as described in the standard text “Protectinggroups in Organic Synthesis”, 2nd Edition (1991) by Greene and Wuts. Theprotective group may also be a polymer resin such as Wang resin or2-chlorotrityl chloride resin.

[0135] Methods of Preparation

[0136] The compounds of the invention may be prepared as outlined belowaccording to any of the following methods. However, the invention is notlimited to these methods, the compounds may also be prepared asdescribed for structurally related compounds in the prior art.

[0137] A. The compounds of Formula I wherein R or R² is, where defined,—OR^(d), —SCOR^(d), —SR^(d), —OSO₂R^(d), NR^(c)COOR^(a), —NR^(c)COR^(a),—NR^(a)CONR^(a)R^(k) or —NR^(c)SO₂R^(d) can be prepared by reaction of acompound of Formula I wherein the respective R or R² group is, forexample, —OH, —SH or —NHR^(a) with a suitable reagent, such as athioate, a sulfonyl halide, an isocyanate, a chloroformate or anaddition reagent for ether, such as alkylhalide or arylhalide. Thereactions can be carried out in accordance with methods known to thoseskilled in the art, or as described in the examples. Suitable referencesare

[0138] “Comprehensive Organic Transformations” R. C. Larock (VCHPublishers Inc.) 1989, p445-448, for the formation of alkyl or arylethers.

[0139] “Advanced Organic Chemistry” J. March (4^(th) edition), JohnWiley & Sons, 407-409, for the formation of thioethers, and 498-499, forthe formation of sulfonates, 417-418, for the formation of amides,411413, for formation of amines.

[0140] B. The compounds of Formula I wherein R or R² is, where defined,—SR^(a) or —SCOR^(a) can be prepared by reaction of a compound ofFormula I wherein the respective R or R² group is, for example,—OSO₂R^(a) with a suitable reagent, respectively. YSR^(a) or YSCOR^(a)(wherein Y is a cation). Suitably the reaction is carried out in aninert solvent, such as DMF or methanol at room temprature with asuitable reducing agent, such as sodium borohydride, LiAlH₄, or DIBAH.

[0141] C. The reduction of the olefin version of the compound of formulaI to the saturated version of a compound of formula I may be carried outby using a wide variety of reducing methods known to reducecarbon-carbon double bonds, such as catalytic hydrogenation in thepresence of an appropriate catalyst, magnesium or sodium amalgam in alower alcohol such as-methanol, or hydrogen transfer reagents such asdiethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

[0142] The catalytic hydrogenation can be conducted in alcohol,cellosolves, protic polar organic solvents, ethers, lower aliphaticacids, and particularly in methanol, ethanol, methoxyethanol,dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, ethylacetate or acetic acid, either used alone or in mixture. Examples of thecatalyst used include palladium black, palladium on activated charcoal,platinum oxide or Wilkinson's catalyst. The reaction can proceed atdifferent temperatures and pressures depending on the reactivity of theaimed reaction.

[0143] In case of hydrogen transfer reaction withdiethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, equimolaramounts of reactants are mixed and the mixture is warmed to melting(140° C.-250° C.) under inert atmosphere or under vacuum. D. Thecompounds of the invention of formula I can be prepared by an alkylationreaction with a compound of formula VIII

[0144] where X¹⁰⁰ is a leaving group, such as halogen, a sulfonate ortriflate, and a compound of formula IXb

[0145] in which formulas E, L, R¹, R², R³, R⁴, X¹⁰⁰ and D″, are asdefined above in and, if desired, followed by removal of any protectivegroups.

[0146] In the alkylation step the compound of Formula IX is reacted witha compound of formula VIII in the presence of one or more bases such aspotassium carbonate, triethylbenzylammonium chloride, sodium hydride,LDA, butyllithium or LHMDS and in a inert solvent such as acetonitrile,DMF or dichloromethane at a suitable temperature and time. The reactioncan be carried out as described in the examples or by standard methodsknown in the literature (Synth. Comm. 19(788) 1167-1175 (1989)).

[0147] The compound of Formula VIII can be prepared from an alcohol offormula X

[0148] wherein E, L, D″ R¹, and R³ are as defined above using standardmethods.

[0149] The compound of Formula X can be prepared from a compound ofFormula III either by reduction with a reducing agent known to convert acarbonyl group to a hydroxyl group such as lithium borohydride or sodiumborohydride or by reaction with an organometallic compound such as anorganolithium or a Grignard reagent by standard methods.

[0150] E. The compounds of the invention of Formula I can be prepared byreaction of a compound of formula VI with a compound of the Formula XI

[0151] in which formulas D″, R¹, R², R³, R⁴, R¹⁰¹ x and R are as definedabove, in a similar reaction as described above, additional protectivegroups may be necessary.

[0152] The compound of Formula XI can be prepared by known methods fromcommercially available starting materials and compounds of formula IV orV.

[0153] The compounds of the invention may be isolated from theirreaction mixtures using conventional techniques.

[0154] Persons skilled in the art will appreciate that, in order toobtain compounds of the invention in an alternative and in someoccasions, more convenient manner, the individual process stepsmentioned hereinbefore may be performed in different order, and/or theindividual reactions may be performed at different stage in the overallroute (i.e. chemical transformations may be performed upon differentintermediates to those associated hereinbefore with a particularreaction).

[0155] In any of the preceding methods of preparation A-E, wherenecessary, hydroxy, amino or other reactive groups may be protectedusing a protecting group, as described in the standard text “Protectivegroups in Organic Synthesis”, 2^(nd) Edition (1991) by Greene and Wuts.The protecting group may also be a resin, such as Wang resin or2-chlorotrityl chloride resin. The protection and deprotection offunctional groups may take place before or after any of the reactionsteps described hereinbefore. Protecting groups may be removed inaccordance to techniques which are well known to those skilled in theart.

[0156] The expression “inert solvent” refers to a solvent which does notreact with the starting materials, reagents, intermediates or productsin a manner which adversely affects the yield of the desired product.

[0157] Pharmaceutical Preparations

[0158] The compounds of the invention will normally be administered viathe oral, parenteral, intravenous, intramuscular, subcutaneous or inother injectable ways, buccal, rectal, vaginal, transdermal and/or nasalroute and/or via inhalation, in the form of pharmaceutical preparationscomprising the active ingredient either as a free acid, or apharmaceutically acceptable organic or inorganic base addition salt, ina pharmaceutically acceptable dosage form. Depending upon the disorderand patient to be treated and the route of administration, thecompositions may be administered at varying doses.

[0159] The compounds of the invention may also be combined with othertherapeutic agents which are useful in the treatment of disordersassociated with the development and progress of atherosclerosis such ashypertension, hyperlipidemias, dyslipidemias, diabetes and obesity.

[0160] Suitable daily doses of the compounds of the invention in thetherapeutic treatment of humans are about 0.001-10 mg/kg body weight,preferably 0.01-1 mg/kg body weight.

[0161] According to a further aspect of the invention there is alsoprovided a pharmaceutical formulation including any of the compounds ofthe invention, or pharmaceutically acceptable derivatives thereof, inadmixture with pharmaceutically acceptable adjuvants, diluents and/orcarriers.

[0162] Pharmacological Properties

[0163] The present compounds of formula (I) are useful for theprophylaxis and/or treatment of clinical conditions associated withreduced sensitivity to insulin (insulin resistance) and associatedmetabolic disorders. These clinical conditions will include, but willnot be limited to, abdominal obesity, arterial hypertension,hyperinsulinaemia, hyperglycaemia, type 2 diabetes mellitus and thedyslipidaemia characteristically appearing with insulin resistance. Thisdyslipidaemia, also known as the atherogenic lipoprotein profile,phenotype B, is characterised by moderately elevated non-esterifiedfatty acids, elevated very low density lipoproteins (VLDL) triglyceriderich particles, low high density lipoproteins (HDL) particle levelscholesterol and the presence of small, dense, low density lipoprotein(LDL) particles. Treatment with the present compounds is expected tolower the cardiovascular morbidity and mortality associated withatherosclerosis. These cardiovascular disease conditions includemacro-angiophaties causing myocardial infarction, cerebrovasculardisease and peripheral arterial insufficiency of the lower extremities.Because of their insulin sensitizing effect the compounds of formula Iare also expected to prevent or delay the development of type 2 diabetesand thus reduce the progress of clinical conditions associated withchronic hyperglycaemia in diabetes type 1 such as the micro-angiophatiescausing renal disease, retinal damage and peripheral vascular disease ofthe lower limbs. Furthermore the compounds may be useful in treatment ofvarious conditions outside the cardiovascular system associated withinsulin resistance like polycystic ovarian syndrome.

WORKING EXAMPLES

[0164]¹H NMR and ¹³C NMR measurements were performed on a Varan Mercury300 or Varian UNITY plus 400, 500 or 600 spectrometers, operating at ¹Hfrequencies of 300, 400, 500 and 600 MHz, respectively, and at ¹³Cfrequencies of 75, 100, 125 and 150 MHz, respectively. Measurements weremade on the delta scale (δ).

[0165] Unless otherwise stated, chemical shifts are given in ppm withthe solvent as internal standard. Abbreviations IRS insulin resistancesyndrome LDA lithium diisopropylamide LHMDS lithiumhexamethyldisilylamine DMF dimethylformamide DEAD diethylazodicarboxylate ADDP azodicarbonyl dipiperidine EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DCCdicyclohexylcarbodiimide HBTUO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphateTBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroboratePyBop benzotriazole-1-yl-oxy-tris-pyrolidino-phosphoniumhexafluorophosphate TEA triethylamine DIPEA diisopropylethylamine TLCthin layer chromatography THF tetrahydrofuran HO-Su N-hydroxysuccinimide Pd/C palladium on charcoal HOBtxH₂O1-hydroxybenzotriazole-hydrate DIBAH diisobutylaluminium hydride DMSOdimethyl sulfoxide t triplet s singlet d doublet q quartet qvint quintetm multiplet br broad bs broad singlet dm doublet of multiplet bt broadtriplet dd doublet of doublet

Example 1

[0166]N′-(2,4-difluorophenyl)-N-(2-{4-[(2S)-2-ethoxy-3-hydroxypropyl]phenyl}ethyl)-N-heptylurea

[0167] (i) Ethyl(2S)-2-ethoxy-3-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)propanoate

[0168] Ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (11.44 g, 48.01mmol) was dissolved in 240 ml dichloromethane and cooled to −40° C. TEA(7.29 g, 72.04 mmol) was added and the temperature was decreased to −60°C. Trifluoromethane sulfonic anhydride (8.88 ml, 52.81 mmol) wasdissolved in 150 ml cold dichloromethane and slowly added to thereaction mixture during 20 minutes. The reaction mixture was stirred at−60° C. for 1.5 hours. The product was washed with cold 1 M potassiumhydrogen sulphate solution, the water phase was washed withdichloromethane, the combined organic phases were washed with saturatedsodium hydrogen carbonate solution and brine, dried (sodium sulphate),filtered and solvent was evaporated in vacuo to give 17.94 g of a brownoil, which was purified by chromatography on silica gel usingheptane:ethyl acetate 2:1 as eluent to give 17.33 g (yield 97.5%) ofpure material.

[0169]¹H-NMR (400 MHz; CDCl₃): 1.13 (t, 3H), 1.20 (t, 3H), 2.96-3.07 (m,2H), 3.28-3.37 (m, 1H), 3.57-3.67 (m, 1H), 3.98 (dd, 1H), 4.15 (q, 2H),7.17 (dm, 2H), 7.32 (dm, 2H).

[0170]¹³C-NMR (100 MHz; CDCl₃): 14.0, 14.9, 38.5, 60.9, 66.3, 79.5,113.9, 117.1, 120.3, 121.0, 123.5, 131.2, 137.9, 141.8, 148.4, 171.9.

[0171] (ii) tert-Butyl(2E)-3-4-{[(2S)-2,3-diethoxy-3-oxopropyl]phenyl}acrylate

[0172] Ethyl(2S)-2-ethoxy-3-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)propanoate

[0173] (0.994 g, 2.69 mmol), t-butyl acrylate (0.78 ml, 5.37 mmol) andtri-o-tolylphosphine (0.302 g, 0.99 mmol) was dissolved in dry DMF (6ml) under argon atmosphere. Palladium acetate (72.4 mg, 0.322 mmol)dissolved in some DMF was added and LiBr (1.2 g, 13.81 mmol) and TEA(dried on potassium hydroxide, 0.543 g, 5.37 mmol) was added using someDMF to rinse it down with (10.74 ml DMF was used in total). The reactionmixture was stirred at 90° C. for 64 hours. After 1 h, more TEA (0.75ml) was added and after 42 hours more TEA (0.75 ml) was added. Water andethyl acetate were added, but the phases became black and separation ofthe phases were impossible, therefor the ethyl acetate phase wasdecanted off and more ethyl acetate was added. This procedure wasrepeated several times. The combined ethyl acetate phases were washedwith water, dried (sodium sulphate), filtered and solvent was evaporatedin vacuo, and the crude product was purified by chromatography on silicagel using dichloromethane:methanol (gradient 0-10% methanol) as eluentto give 0.7 g (yield 75%) of the desired product.

[0174]¹H-NMR (400 MHz; CDCl₃): 1.15 (t, 3H), 1.21 (t, 3H), 1.53 (s, 9H),2.99-3.04 (m, 2H), 3.30-3.39 (m, 1H), 3.57-3.66 (m, 1H), 4.01 (dd, 1H),4.16 (q, 2H), 6.33 (d, 1H), 7.25 (dm, 2H), 7.43 (dm, 2H), 7.56 (d, 1H).

[0175]¹³C-NMR (100 MHz; CDCl₃): 14.1, 15.0, 28.2, 39.1, 60.9, 66.2,79.8, 80.4, 119.7, 127.8, 129.9, 133.1, 139.4, 143.3, 166.3, 172.2.

[0176] (iii) Ethyl(2S)-2-ethoxy-3-[4-(3-{tert-butoxy}-3-oxypropyl)phenyl]propanoate

[0177] tert-Butyl(2E)-3-{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenyl}acrylate (0.614 g, 1.76mmol) was hydrogenated for 1.5 hours at atmospheric pressure in ethanol(35 ml) using Pd/C (wet, 5%,) as catalyst. The mixture was filtered onhyflo and solvent was evaporated in vacuo to give 0.447 g (yield 72%) ofthe desired product.

[0178]¹H-NMR (500 MHz; CDCl₃): 1.13 (t, 3H), 1.19, (t, 3H), 1.39 (s,9H), 2.49 (t, 2H), 2.85 (t, 2H), 2.93-2.97 (m, 2H), 3.28-3.36 (m, 1H),3.54-3.61 (m, 1H), 3.94-3.99 (m, 1H), 4.13 (m, 2H), 7.07-7.11 (m, 2H),7.11-7.15 (m, 2H).

[0179]¹³C-NMR (125 MHz; CDCl₃): 14.1, 14.9, 27.9, 30.6, 36.9, 38.8,60.6, 66.0, 80.1, 128.1, 129.3, 134.8, 138.9, 172.1, 172.3. (1 carbon ismissing)

[0180] (iv) 3-{4-[(2S)-2,3-Diethoxy-3-oxopropyl]phenyl}propanoic acid

[0181] Trifluoroacetic acid (2.20 ml, 28.45 mmol) was added to asolution of ethyl(2S)-2-ethoxy-3-[4-(3-{tert-butoxy)}-3-oxypropyl)phenyl]propanoate (0.43g, 1.22 mmol) in dichloromethane (4 ml) and stirred for 3 hours at roomtemperature. Evaporation of solvent in vacuo gave 0.36 g (yield 101%,contains some remaining TFA) of the desired product.

[0182]¹H-NMR (500 MHz; CDCl₃): 1.15 (t, 3H), 1.22 (t, 3H), 2.72 (t, 2H),2.95 (t, 2H), 3.02-3.06 (m, 2H), 3.40-3.49 (m, 1H), 3.61-3.70 (m, 1H),4.124.16 (m, 1H), 4.21 (q, 2H), 7.12-7.18 (m, 4H).

[0183]¹³C-NMR (125 MHz; CDCl₃): 13.7, 14.4, 30.0, 35.5, 38.5, 62.2,66.9, 80.2, 128.2, 129.5, 134.4, 138.4, 174.3, 180.2.

[0184] (v) Ethyl(2S)-3-[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)phenyl]-2-ethoxypropanoate

[0185] 3-{4-[(2S)-2,3-Diethoxy-3-oxopropyl]phenyl}propanoic acid (0.13g, 0.44 mmol) and dry TEA (47 mg, 0.46 mmol) were dissolved in drybenzene (1.14 ml) under nitrogen atmosphere and stirred for someminutes. Diphenylphosphoryl azide was added and the mixture was refluxedfor 30 minutes. Dry benzylalcohol (57 mg, 0.53 mmol) was added and themixture was refluxed for 20 hours and then stirred at room temperaturefor 3.5 hours. More benzylalcohol was added (0.15 ml) and the mixturewas refluxed for 19 hours more, thereafter solvent was evaporated invacuo and the crude product was purified by chromatography on silica gelusing heptane:ethyl acetate 3:1 as eluent to give 118 mg (yield 67%) ofthe desired product.

[0186]¹H-NMR (400 MHz; CDCl₃): 1.16 (t, 3H), 1.21 (t, 3H), 2.79 (t, 2H),2.98 (dd, 2H), 3.31-3.40 (m, 1H), 3.40-3.48 (m, 2H), 3.56-3.65 (m, 1H),3.97-4.02 (m, 1H), 4.16 (q, 2H), 5.09 (s, 2H), 7.09 (dm, 2H), 7.17 (dm,2H), 7.32-7.38 (m, 5H).

[0187]¹³C-NMR (75 MHz; CDCl₃): 14.1, 15.0, 35.6, 38.8, 42.1, 60.8, 66.1,66.6, 80.1, 128.0, 128.4, 128.5, 128.6, 129.6, 135.3, 136.5, 136.8,156.2, 172.4.

[0188] (vi) Ethyl (2S)-3-[4-(2-aminoethyl)phenyl]-2-ethoxypropanoate

[0189] Ethyl(2S)-3-[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)phenyl]-2-ethoxypropanoate(2.45 g, 6.14 mmol) was hydrogenated for 2.5 hours at atmosphericpressure in ethyl acetate (51 ml) using Pd/C (1 spoon) as catalyst.After filtration on hyflo, the solvent was evaporated in vacuo. Thecrude product was purified by chromatography on silica gel usingTHF:methanol (NH₃-saturated) (gradient 25:1-1:25) as eluent. The firstfractions containing the product was filtered on Millipore filter andcombined with the later fractions containing product to give 0.84 g(yield 52%, including a by-product) of the desired product.

[0190]¹H-NMR (400 MHz; CDCl₃): 1.15 (t, 3H), 1.20 (t, 3H), 1.82 (bs,2NH), 2.69-2.78 (m, 2H), 2.9-3.0 (m, 4H), 3.30-3.41 (m, 1H), 3.54-3.64(m, 1H), 3.97-4.03 (m, 1H), 4.10-4.20 (m, 2H), 7.07-7.17 (m, 4H).

[0191]¹³C-NMR (100 MHz; CDCl₃): 14.1, 15.0, 38.8, 39.3, 43.3, 60.7,66.1, 80.1, 128.7, 129.6, 135.0, 137.8, 172.4.

[0192] (vii) Ethyl(2S)-2-ethoxy-3-{4-[2-(heptanoylamino)ethyl]phenyl}propanoate

[0193] Ethyl (2S)-3-[4-(2-aminoethyl)phenyl]-2-ethoxypropanoate (320 mg1.206 mmol) and heptanoic acid (157 mg, 1.206 mmol) were mixed in DCM(10 ml). EDC (243 mg, 1.266 mmol) was added and then DMAP (147 mg, 1.206mmol) was added. The mixture was stirred at room temperature overnight.It was then washed with 1% hydrochloric acid, water, 1% sodiumhydrogencarbonate aqueous solution, water and brine and dried withmagnesium sulfate. The solvent was evaporated in vacuum. Chromatographyof the residue on a column (ISOLUTE, SI, 2 g/6 ml) using DCM, MeOH/DCM(0.5:99.5) and then MeOH/DCM (1:99) as eluant gave 166 mg desiredproduct, yield 37%.

[0194]¹H NMR (400 MHz, CDCl₃): δ 0.89 (t, J=7 Hz, 3H), 1.18 (t, J=7 Hz,3H), 1.24 (t, J=7 Hz, 3H), 1.26-1.35 (m, 6H), 1.56-1.64 (m, 2H), 2.12(t, J=7 Hz, 2H), 2.79 (t, J=7 Hz, 2H), 2.99-3.02 (m, 2H), 3.34-3.41 (m,1H), 3.51 (q, J=7 Hz, 2H), 3.59-3.66 (m, 1H), 4.02 (dd, J=7, 6 Hz, 1H),4.19 (q, J=7 Hz, 2H), 5.43 (s, br, 1H), 7.12 (d, J=8 Hz, 2H) and 7.20(d, J=8 Hz, 2H).

[0195] (viii)(2S)-2-Ethoxy-3-{4-[2-(heptylamino)ethyl]phenyl}propan-1-olhydrochloride

[0196] Ethyl(2S)-2-ethoxy-3-{4-[2-(heptanoylamino)ethyl]phenyl}propanoate (204 mg,0.54 mmol) in tetrahydrofuran (5 ml, dry) was cooled in an ice-bath.Borane methylsulfide complexe (2 M in ether, 0.7 ml) was added. Thecooling bath was removed after 15 minutes. The reaction mixture washeated to reflux gently for 6 hours and then cooled down to roomtemperature. Hydrochloric acid (10%, 0.3 ml) was dropped in. The mixturewas stirred overnight and then evaporated in vacuum to dry.Chromatography of the residue on a column (ISOLUTE, SI, 2 g/6 ml) usingDCM, MeOH (1:99) and then MeOH/DCM (2:98) as eluant gave two products.51 mg of (2S)-2-Ethoxy-3-{4-[2-(heptylamino)ethyl]phenyl}propan-1-olhydrochloride was obtained as one of them.

[0197]¹H NMR (400 MHz, CDCl₃): δ 0.84 (t, J=7 Hz, 3H), 1.17 (t, J=7 Hz,3H), 1.21-1.39 (m, 8H), 1.88-1.96(m, 2H), 2.71 (dd, J=14, 8 Hz, 1H),2.84 (dd, J=14, 6 Hz, 1H), 2.93-2.97 (m, 2H), 3.12-3.28 (m, 4H),3.41-3.62 (m, 5H), 7.13 (d, J=8 Hz, 2H), 7.16(d, J=8 Hz, 2H) and 9.71(s, br, 2H).

[0198] (ix)N′-(2,4-difluorophenyl)-N-(2-{4-[(2S)-2-ethoxy-3-hydroxypropyl]phenyl}ethyl)-N-heptylurea

[0199] (2S)-2-Ethoxy-3-{4-[2-(heptylamino)ethyl]phenyl}propan-1-olhydrochloride (21 mg, 0.059 mmol) and triethyl amine (0.009 ml, 0.065mmol) were mixed in DCM. 2,4-Di fluorophenyl isocyanate (9.2 mg, 0.059mmol) was added. The mixture was stirred overnight. Water was added. Theorganic phase was washed with brine and dried with magnesium sulfate.The solvent was evaporated in vacuum and an oil mixture was left.Chromatography of the oil mixture on a column (ISOLUTE, SI, 200 mg/1 ml)using DCM and MeOH/DCM (1:99) as eluant gave 17 mg desired product,yield 60%.

[0200]¹H NMR (400 MHz, CDCl₃): δ 0.90 (t, J=7 Hz, 3H), 1.19 (t, J=7 Hz,3H), 1.27-1.35 (m, 8H), 1.59-1.66 (m, 2H), 1.99 (t, J=6 Hz, 1H), 2.72(dd, J=14, 8 Hz, 1H), 2.86 (dd, J=14, 6 Hz, 1H), 2.91 (t, J=7 Hz, 2H),3.24 (t, J=7.7 Hz, 2H), 3.40-3.63 (m, 7H), 6.31 (s, br, 1H), 6.81-6.87(m, 2H), 7.17 (s, 4H) and 8.01-8.07 (m, 1H).

[0201]¹³C NMR (100 MHz, CDCl₃): δ 14.0, 15.50, 22.53, 26.94, 28.54,29.0, 31.71, 34.55, 36.99, 48.16, 49.98, 63.60, 65.17, 80.92, 103.11 (t,²J_(CF)=24 Hz), 110.98 (d, ²J_(CF)=25 Hz), 122.42 (d, ³J_(CF)=8 Hz),124.02 (m), 128.79 (2C), 129.72 (2C), 136.50, 136.67, 152.28 (d,¹J_(CF)=239 Hz), 153.48 and 157.60 (d, ¹J_(CF)=233 Hz).

[0202] Biological Activity

[0203] The biological activity of the compounds of the invention isdemonstrable in obese diabetic mice of the Umeå ob/ob strain. Groups ofmice receive the test compound by gavage once daily for 7 days. On thelast day of the experiment the animals are anesthetized 2 h after dosein a non-fed state and blood is collected from an incised artery. Plasmais analyzed for concentration of glucose, insulin and triglycerides. Agroup of untreated obese diabetic mice of the same age serve as control.The weight of the mice is measured before and after the experiment andthe obtained weight gain is compared to the weight gain of the controlanimals. The individual values for glucose, insulin and triglyceridelevels of the mice from the test group are expressed as the percentrange of the corresponding values from the control group.

[0204] The desired “therapeutic effect” is calculated as the averagepercent reduction of the three variables glucose, insulin andtriglycerides below the levels in the control animals.

1. A compound of the general formula (I)

and stereo and optical isomers and racemates thereof as well aspharmaceutically acceptable salts, prodrugs, solvates and crystallineforms thereof, in which formula a is situated in the ortho, meta or paraposition and represents

wherein r is cyano, when x is 0, and when x is I then r is: —BR^(a),OCOR^(a) or SCOR^(a), wherein B is O, S, SO or SO₂ wherein R^(a)represents hydrogen, alkyl, aryl, alkylaryloxy or alkylaryl and whereinthe alkyl, aryl or alkylaryl group is optionally substituted one or moretimes by R^(b), wherein R^(b) represents alkyl, aryl, alkylaryl, cyano,—NR^(c)R^(c), ═O, halogen, —OH, —SH, -Oalkyl, -Oaryl, -Oalkylaryl,—COR^(c), —SR^(d), —SOR^(d), or —SO₂R^(d) (preferably R^(b) is selectedfrom alkyl, aryl, alkylaryl, cyano, —NH₂, ═O, halogen and —OH), whereinR^(c) represents hydrogen, alkyl, aryl or alkylaryl and R^(d) representsalkyl, aryl or alkylaryl; —BB¹R^(a), wherein B¹ is O when B is S, SO orSO₂ or B¹ is S, SO or SO₂ when B is O, and wherein B and R^(a) are asdefined above; or alternatively R is —NR^(a)R^(a), wherein each R^(a) isthe same or different and wherein R^(a) is defined above; R² representsalkyl, halogen, aryl, alkylaryl, alkenyl, alkynyl, nitro or cyano andwherein the alkyl, aryl, alkenyl, alkylaryl and alkynyl group isoptionally substituted by R^(b), wherein R^(b) is as defined above;—BR^(a) wherein B and R^(a) are as defined above; —SO₂NR^(a)R^(f),wherein R^(f) represents hydrogen, alkyl, acyl, aryl or alkylaryl andR^(a) is as defined above; —SO₂OR^(a), wherein R^(a) is as definedabove; —OCONR^(f)R^(a), wherein R^(f) and R^(a) are as defined above;—NR^(c)COOR^(d), wherein R^(c) and R^(d) are as defined above;—NR^(c)COR^(a), wherein R^(c) and R^(a) are as defined above;—CONR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;—NR^(c)SO₂R^(d), wherein R^(c) and R^(d) are as defined above;—NR^(c)CONR^(a)R^(k), wherein R^(a) and R^(c) are as defined above andR^(k) represents hydrogen, alkyl, aryl, or alkylaryl; alternatively R²is —NR^(c)R^(a), wherein R^(c) and R^(a) are as defined above; R¹, R³and R⁴ are the same or different and each represents hydrogen, alkyl,aryl, alkenyl, alkynyl, cyano, halogen or alkylaryl wherein the alkyl,aryl, alkenyl or alkynyl group is optionally substituted by R^(b); x isan integer 0 or 1 (preferably x is 1); E represents a group of formula i

or a group of formula ii

wherein X is S, O, NR^(Z) wherein R^(Z) is as defined below, CH═N orN═CH and Y represents CH or N; or X represents —CH═CH— and Y representsN; or E represents a group of formula iii

wherein X is S, O, NR^(z), —CH═N or —N═CH and Y represents CH or N; or Xrepresents —CH═CH— and Y represents N wherein R^(z) represents hydrogen,alkyl, aryl, alkyloxyaryl, alkylbiphenylyl, alkoxyalklylaryl,acylbiphenylyl, alkylphthalimido, SO₂R^(Z), COR^(d) or alkylaryl(preferably R^(Z) is selected from hydrogen, alkyl and alkyaryl) andwherein the alkyl, aryl, alkyloxyaryl or alkylaryl group is optionallysubstituted one or more times by R^(b), wherein R^(b) represents alkyl,aryl, alkylaryl, cyano, —NR^(c)R^(c), ═O, halogen, —OH, —SH, -Oalkyl,-Oaryl, -Oalkylaryl, —COR^(c), —SR^(d), —SOR^(d), or —SO₂R^(d)(preferably R^(b) is selected from alkyl, aryl, alkylaryl, cyano, —NH₂,═O, halogen and —OH), wherein R^(c) represents hydrogen, alkyl, aryl oralkylaryl and R^(d) represents alkyl, aryl or alkylaryl; or E representsa group of formula iv C3-C8cycloalkyl iv or E represents a group offormula v

which is linked to L through the nitrogen atom; or E represents a groupof formula vi

or E represents a group of formula vii

wherein D represents H, alkyl, acyl, aryl, alkylaryl, halogen, —CN andNO₂, wherein the alkyl, aryl, or alkylaryl group is optionallysubstituted by Rb; —NR^(c)COOR^(a), wherein R^(c) and R^(a) are asdefined above; —NR^(c)COR^(a), wherein R^(c) and R^(a) are as definedabove; —NR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;—NR^(c)SO₂R^(d), wherein R^(c) and R^(d) are as defined above;—NR^(c)CONR^(k)R^(c), wherein R^(a), R^(c) and R^(k) are as definedabove; —NR^(c)CSNR^(a)R^(k), wherein R^(a), R^(c) and R^(k) are asdefined above; —OR^(a), wherein R^(a) is as defined above; —OSO₂R^(d),wherein R^(d) is as defined above; —SO₂R^(d), wherein R^(d) is asdefined above; —SOR^(d), wherein R^(d) is as defined above; —SR^(c),wherein R^(c) is as defined above; —SO₂NR^(a)R^(f), wherein R^(f) andR^(a) are as defined above; —SO₂OR^(a), wherein R^(a) is as definedabove; —CONR^(c)R^(a), wherein R^(c) and R^(a) are as defined above;—OCONR^(f)R^(a), wherein R^(f) and R^(a) are as defined above; m is aninteger 0 or 1 (preferably m is 1); D′ represents hydrogen, alkyl, acyl,aryl, alkylaryl, halogen, —CN, —NO₂, —NR^(f)R^(b), wherein R^(f) andR^(b) are as defined above; —OR^(f), wherein R^(f) is as defined above;—OSO₂R^(d), wherein R^(d) is as defined above; CH═CH—COOR^(c) whereinR^(c) is as defined above; D″ is represents hydrogen, alkyl, acyl, aryl,alkylaryl, halogen; —CN, —NO₂, —NR^(f)R^(b) wherein R^(f) and R^(b) areas defined above; —OR^(f), wherein R^(f) is as defined above;—OSO₂R^(d), wherein R^(d) is as defined above; L represents O or analkylene chain having from 1 to 6 carbon atoms optionally interrupted orterminated by one or more of the following O, S, SO, SO₂, CO, NR^(t),CONR^(t), NR^(t)CO, OC(O)NR^(t), NR^(t)C(O)O, SO₂NR^(t), R^(t)NSO₂ orR^(t)N—CO—NR^(t) provided that they are not attached to each other andwherein the alkylene chain carbons may be substituted by one or morealkyl, hydroxy, aryl, aryloxy, arylthio, alkylaryl, cyano, NR^(c)R^(c),halo, SH, Oalkylaryl, COR^(c), —COR^(c), —SR^(d), —SOR^(d), or—SO₂R^(d), or alkoxy and with the proviso that when E is a group offormula i then L does not represent [CH₂]_(n)—CH₂—O in which n is aninteger from 1 to 6; and R^(t) represents H, alkyl, aryl, alkylaryl,alkylcycloalkyl, or alkylbiphenylyl wherein each alkyl chain may besubstituted by one or more hydroxy or alkoxy and is optionallyinterrupted by one or more O provided that two hetero atoms are notattached to the same carbon atom.
 2. A compound according to claim 1wherein L represents O, a C1, C2, C3, C4 or C5 alkylene chain or a groupof formula (CH₂)_(n)Z¹(CH₂)_(b)Z² wherein a is 0,1, 2 or 3; Z¹ is absentor represents O, S, SO, SO₂, CO, NR^(t), CONR^(t), NR^(t)CO,OC(O)NR^(t), NR^(t)C(O)O, SO₂NR^(t), R^(t)NSO₂ or R^(t)N—CO—NR^(t), b is1, 2 or 3 and Z² is absent or represents O, S, SO, SO₂,CO, NR^(t),CONR^(t), NR^(t)CO, OC(O)NR^(t), NR^(t)C(O)O, R^(t)N—CO—NR^(t) whereinR^(t) is as defined above and all of the alkylene chains are optionallysubstituted by one or more of the following alkyl, hydroxy, aryl,aryloxy, arylthio, alkylaryl, cyano, NR^(c)R^(c), halo, SH, Oalkylaryl,COR^(c), —COR^(c), —SR^(d), —SOR^(d), or —SO₂R^(d), or alkoxy whereinR^(d) is as defined above, provided that Z¹ and Z² are not absentsimultaneously.
 3. A compound of formula I as claimed in claim 1 for useas a medicament.
 4. A pharmaceutical formulation comprising a compoundof formula I, as defined in claim 1 and a pharmaceutically acceptableadjuvant, diluent or carrier.
 5. Use of a compound of formula I, asdefined in claim 1 in the preparation of a medicament for the treatmentor prophylaxis of conditions associated with a patient having reducedsensitivity to insulin.